Repercussion of Megakaryocyte-Specific Gata1 Loss on Megakaryopoiesis and the Hematopoietic Precursor Compartment

Marjolein Meinders, Mark Hoogenboezem, Maaike R Scheenstra, Iris M De Cuyper, Petros Papadopoulos, Tamás Németh, Attila Mócsai, Timo K van den Berg, Taco W. Kuijpers, Laura Gutiérrez

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

During hematopoiesis, transcriptional programs are essential for the commitment and differentiation of progenitors into the different blood lineages. GATA1 is a transcription factor expressed in several hematopoietic lineages and essential for proper erythropoiesis and megakaryopoiesis. Megakaryocyte-specific genes, such as GP1BA, are known to be directly regulated by GATA1. Mutations in GATA1 can lead to dyserythropoietic anemia and pseudo gray-platelet syndrome. Selective loss of Gata1 expression in adult mice results in macrothrombocytopenia with platelet dysfunction, characterized by an excess of immature megakaryocytes. To specifically analyze the impact of Gata1 loss in mature committed megakaryocytes, we generated Gata1-Lox|Pf4-Cre mice (Gata1cKOMK). Consistent with previous findings, Gata1cKOMK mice are macrothrombocytopenic with platelet dysfunction. Supporting this notion we demonstrate that Gata1 regulates directly the transcription of Syk, a tyrosine kinase that functions downstream of Clec2 and GPVI receptors in megakaryocytes and platelets. Furthermore, we show that Gata1cKOMK mice display an additional aberrant megakaryocyte differentiation stage. Interestingly, these mice present a misbalance of the multipotent progenitor compartment and the erythroid lineage, which translates into compensatory stress erythropoiesis and splenomegaly. Despite the severe thrombocytopenia, Gata1cKOMK mice display a mild reduction of TPO plasma levels, and Gata1cKOMK megakaryocytes show a mild increase in Pf4 mRNA levels; such a misbalance might be behind the general hematopoietic defects observed, affecting locally normal TPO and Pf4 levels at hematopoietic stem cell niches.

Original languageEnglish
Pages (from-to)e0154342
JournalPLoS ONE
Volume11
Issue number5
DOIs
Publication statusPublished - 2016

Cite this

Meinders, M., Hoogenboezem, M., Scheenstra, M. R., De Cuyper, I. M., Papadopoulos, P., Németh, T., ... Gutiérrez, L. (2016). Repercussion of Megakaryocyte-Specific Gata1 Loss on Megakaryopoiesis and the Hematopoietic Precursor Compartment. PLoS ONE, 11(5), e0154342. https://doi.org/10.1371/journal.pone.0154342
Meinders, Marjolein ; Hoogenboezem, Mark ; Scheenstra, Maaike R ; De Cuyper, Iris M ; Papadopoulos, Petros ; Németh, Tamás ; Mócsai, Attila ; van den Berg, Timo K ; Kuijpers, Taco W. ; Gutiérrez, Laura. / Repercussion of Megakaryocyte-Specific Gata1 Loss on Megakaryopoiesis and the Hematopoietic Precursor Compartment. In: PLoS ONE. 2016 ; Vol. 11, No. 5. pp. e0154342.
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Meinders, M, Hoogenboezem, M, Scheenstra, MR, De Cuyper, IM, Papadopoulos, P, Németh, T, Mócsai, A, van den Berg, TK, Kuijpers, TW & Gutiérrez, L 2016, 'Repercussion of Megakaryocyte-Specific Gata1 Loss on Megakaryopoiesis and the Hematopoietic Precursor Compartment' PLoS ONE, vol. 11, no. 5, pp. e0154342. https://doi.org/10.1371/journal.pone.0154342

Repercussion of Megakaryocyte-Specific Gata1 Loss on Megakaryopoiesis and the Hematopoietic Precursor Compartment. / Meinders, Marjolein; Hoogenboezem, Mark; Scheenstra, Maaike R; De Cuyper, Iris M; Papadopoulos, Petros; Németh, Tamás; Mócsai, Attila; van den Berg, Timo K; Kuijpers, Taco W.; Gutiérrez, Laura.

In: PLoS ONE, Vol. 11, No. 5, 2016, p. e0154342.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Repercussion of Megakaryocyte-Specific Gata1 Loss on Megakaryopoiesis and the Hematopoietic Precursor Compartment

AU - Meinders, Marjolein

AU - Hoogenboezem, Mark

AU - Scheenstra, Maaike R

AU - De Cuyper, Iris M

AU - Papadopoulos, Petros

AU - Németh, Tamás

AU - Mócsai, Attila

AU - van den Berg, Timo K

AU - Kuijpers, Taco W.

AU - Gutiérrez, Laura

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AB - During hematopoiesis, transcriptional programs are essential for the commitment and differentiation of progenitors into the different blood lineages. GATA1 is a transcription factor expressed in several hematopoietic lineages and essential for proper erythropoiesis and megakaryopoiesis. Megakaryocyte-specific genes, such as GP1BA, are known to be directly regulated by GATA1. Mutations in GATA1 can lead to dyserythropoietic anemia and pseudo gray-platelet syndrome. Selective loss of Gata1 expression in adult mice results in macrothrombocytopenia with platelet dysfunction, characterized by an excess of immature megakaryocytes. To specifically analyze the impact of Gata1 loss in mature committed megakaryocytes, we generated Gata1-Lox|Pf4-Cre mice (Gata1cKOMK). Consistent with previous findings, Gata1cKOMK mice are macrothrombocytopenic with platelet dysfunction. Supporting this notion we demonstrate that Gata1 regulates directly the transcription of Syk, a tyrosine kinase that functions downstream of Clec2 and GPVI receptors in megakaryocytes and platelets. Furthermore, we show that Gata1cKOMK mice display an additional aberrant megakaryocyte differentiation stage. Interestingly, these mice present a misbalance of the multipotent progenitor compartment and the erythroid lineage, which translates into compensatory stress erythropoiesis and splenomegaly. Despite the severe thrombocytopenia, Gata1cKOMK mice display a mild reduction of TPO plasma levels, and Gata1cKOMK megakaryocytes show a mild increase in Pf4 mRNA levels; such a misbalance might be behind the general hematopoietic defects observed, affecting locally normal TPO and Pf4 levels at hematopoietic stem cell niches.

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Meinders M, Hoogenboezem M, Scheenstra MR, De Cuyper IM, Papadopoulos P, Németh T et al. Repercussion of Megakaryocyte-Specific Gata1 Loss on Megakaryopoiesis and the Hematopoietic Precursor Compartment. PLoS ONE. 2016;11(5):e0154342. https://doi.org/10.1371/journal.pone.0154342